title: Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB.
abstract: Mutants of neuroserpin are retained as polymers within the endoplasmic reticulum (ER) of neurones to cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. The cellular consequences are unusual in that the ordered polymers activate the ER overload response (EOR) in the absence of the canonical unfolded protein response. We use both cell lines and Drosophila models to show that the G392E mutant of neuroserpin that forms polymers is degraded by UBE2j1 E2 ligase and Hrd1 E3 ligase while truncated neuroserpin, a protein that lacks 132 amino acids, is degraded by UBE2g2 (E2) and gp78 (E3) ligases. The degradation of G392E neuroserpin results from SREBP-dependent activation of the cholesterol biosynthetic pathway in cells that express polymers of neuroserpin (G392E). Inhibition of HMGCoA reductase, the limiting enzyme of the cholesterol biosynthetic pathway, reduced the ubiquitination of G392E neuroserpin in our cell lines and increased the retention of neuroserpin polymers in both HeLa cells and primary neurones. Our data reveal a reciprocal relationship between cholesterol biosynthesis and the clearance of mutant neuroserpin. This represents the first description of a link between sterol metabolism and modulation of the proteotoxicity mediated by the EOR.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research (CIMR), Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Benoit D
authors.initials: BD
authors.lastname: Roussel
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Newton
authors.forename: Elke
authors.initials: E
authors.lastname: Malzer
authors.forename: Nikol
authors.initials: N
authors.lastname: Simecek
authors.forename: Imran
authors.initials: I
authors.lastname: Haq
authors.forename: Sally E
authors.initials: SE
authors.lastname: Thomas
authors.forename: Marian L
authors.initials: ML
authors.lastname: Burr
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
authors.forename: Damian C
authors.initials: DC
authors.lastname: Crowther
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Marciniak
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006367:HeLa Cells; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism*; D058767:Protein Unfolding; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D056811:Unfolded Protein Response; D000097522:Neuroserpin
chemical_list: D002784:Cholesterol; D050505:Mutant Proteins; D009479:Neuropeptides; D011108:Polymers; D015843:Serpins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D000097522:Neuroserpin